Addition of interleukin-6 inhibition with tocilizumab to standard graft-versus-host disease prophylaxis after allogeneic stem-cell transplantation: a phase 1/2 trial

Kennedy, Glen A., Varelias, Antiopi, Vuckovic, Slavica, Le Texier, Laetitia, Gartlan, Kate H., Zhang, Ping, Thomas, Gethin, Anderson, Lisa, Boyle, Glen, Cloonan, Nicole, Leach, Justine, Sturgeon, Elise, Avery, Judy, Olver, Stuart D., Lor, Mary, Misra, Ashish K., Hutchins, Cheryl, Morton, A. James, Durrant, Simon T. S., Subramoniapillai, Elango, Butler, Jason P., Curley, Cameron I., MacDonald, Kelli P. A., Tey, Siok-Keen and Hill, Geoffrey R. (2014) Addition of interleukin-6 inhibition with tocilizumab to standard graft-versus-host disease prophylaxis after allogeneic stem-cell transplantation: a phase 1/2 trial. The Lancet Oncology, 15 13: 1451-1459. doi:10.1016/S1470-2045(14)71017-4


Author Kennedy, Glen A.
Varelias, Antiopi
Vuckovic, Slavica
Le Texier, Laetitia
Gartlan, Kate H.
Zhang, Ping
Thomas, Gethin
Anderson, Lisa
Boyle, Glen
Cloonan, Nicole
Leach, Justine
Sturgeon, Elise
Avery, Judy
Olver, Stuart D.
Lor, Mary
Misra, Ashish K.
Hutchins, Cheryl
Morton, A. James
Durrant, Simon T. S.
Subramoniapillai, Elango
Butler, Jason P.
Curley, Cameron I.
MacDonald, Kelli P. A.
Tey, Siok-Keen
Hill, Geoffrey R.
Title Addition of interleukin-6 inhibition with tocilizumab to standard graft-versus-host disease prophylaxis after allogeneic stem-cell transplantation: a phase 1/2 trial
Journal name The Lancet Oncology   Check publisher's open access policy
ISSN 1474-5488
1470-2045
Publication date 2014-12-01
Year available 2014
Sub-type Article (original research)
DOI 10.1016/S1470-2045(14)71017-4
Volume 15
Issue 13
Start page 1451
End page 1459
Total pages 9
Place of publication London, United Kingdom
Publisher The Lancet Publishing Group
Language eng
Formatted abstract
Background

Interleukin 6 mediates graft-versus-host disease (GVHD) in experimental allogeneic stem-cell transplantation (allogeneic SCT) and represents an attractive therapeutic target. We aimed to assess whether the humanised anti-interleukin-6 receptor monoclonal antibody, tocilizumab, could attenuate the incidence of acute GVHD.

Methods

We undertook a single-group, single-institution phase 1/2 study at the Royal Brisbane and Women's Hospital Bone Marrow Transplantation unit, QLD, Australia. Eligible patients were 18–65 years old and underwent T-replete HLA-matched allogeneic SCT with either total body irradiation-based myeloablative or reduced-intensity conditioning from unrelated or sibling donors. One intravenous dose of tocilizumab (8 mg/kg, capped at 800 mg, over 60 mins' infusion) was given the day before allogeneic SCT along with standard GVHD prophylaxis (cyclosporin [5 mg/kg per day on days −1 to +1, then 3 mg/kg per day to maintain therapeutic levels (trough levels of 140–300 ng/mL) for 100 days plus methotrexate [15 mg/m2 on day 1, then 10 mg/m2 on days 3, 6, and 11]). The primary endpoint was incidence of grade 2–4 acute GVHD at day 100, assessed and graded as per the Seattle criteria. Immunological profiles were compared with a non-randomised group of patients receiving allogeneic SCT, but not treated with tocilizumab. This trial is registered with the Australian and New Zealand Clinical Trials Registry, number ACTRN12612000726853.

Findings

Between Jan 19, 2012, and Aug 27, 2013, 48 eligible patients receiving cyclosporin and methotrexate as GVHD prophylaxis were enrolled into the study. The incidence of grade 2–4 acute GVHD in patients treated with tocilizumab at day 100 was 12% (95% CI 5–24), and the incidence of grade 3–4 acute GVHD was 4% (1–13). Grade 2–4 acute GVHD involving the skin developed in five (10%) patients of 48 treated with tocilizumab, involving the gastrointestinal tract in four (8%) patients; there were no reported cases involving the liver. Low incidences of grade 2–4 acute GVHD were noted in patients receiving both myeloablative total body irradiation-based conditioning (12% [95% CI 2–34) and fludarabine and melphalan reduced-intensity conditioning (12% [4–27]). Immune reconstitution was preserved in recipients of interleukin-6 receptor inhibition, but qualitatively modified with suppression of known pathogenic STAT3-dependent pathways.

Interpretation

Interleukin 6 is the main detectable and dysregulated cytokine secreted after allogeneic SCT and its inhibition is a potential new and simple strategy to protect from acute GVHD despite robust immune reconstitution; a randomised, controlled trial assessing tocilizumab in addition to standard GVHD prophylaxis in these patients is warranted.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
UQ Diamantina Institute Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 53 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 50 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Tue, 02 Dec 2014, 14:46:22 EST by System User on behalf of UQ Diamantina Institute